Development of a vaccine against HIV is the only hope of controlling the AIDS pandemic. However, although cell mediated immune (CMI) responses have been shown to be important for controlling the virus in infected persons, identification and success of a vaccine that could induce these responses has remained elusive. The ability of DNA vaccine to elicit CMI response and its safe profile makes plasmid DNA an attractive alternative to traditional vaccines. However, despite some success of DNA based immunization through intramuscular route, it shows poor immunogenicity especially in nonhuman primates &humans. Recent studies have highlighted the intestinal mucosa as the primary site of HIV-infection and therefore vaccine strategies should be aimed at induction of mucosal immunity. We expect that oral DNA vaccination will, thus, be the most effective approach in providing protection against HIV. Two specific aims are proposed in this project. In the first aim we will fabricate and characterize target specific poly (lactide-co-glycolide) (PLGA) nanoparticles encapsulated with broad spectrum simian-HIV (SHIV) DNA vaccine followed by screening for the expression of HIV-1 proteins in cell culture. This will allow identification of viable gene delivery vector(s) for oral delivery of DNA vaccine in mice. In the second aim we will investigate the ability of the orally administered nanoparticles to express genes in the APCs of gastrointestinal tract and then test the immune responses generated against the SHIV-DNA vaccine in mice. We expect that this approach will strongly generate both mucosal and systemic immune responses with a single oral immunization of a relatively small dose of DNA vaccine. The long term goal of this proposal is to develop DNA vaccine encapsulated nanoparticles, as an effective oral vaccination strategy against HIV-infection. PUBLIC HEALTH RELEVANCE: The proposed research will augment current efforts to develop an effective prophylactic vaccine against HIV, the only hope of controlling the AIDS pandemic, thus, directly addressing the goals of the NIH for improving human health through a multidisciplinary effort to prevent infectious disease.